Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension

ABSTRACT

The invention relates to ophthalmological compositions for topical treatment of glaucoma or ocular hypertension comprising an effective intraocular pressure reducing amount of a prostaglandin derivative of PGA, PGB, PGD, PGE or PGF, in which the omega chain contains a ring structure, in an ophthalmologically compatible carrier. The invention further relates to the preparation of said compositions and their use for treatment of glaucoma or ocular hypertension.

[0001] The invention is concerned with the use of prostaglandinderivatives of PGA, PGB, PGD, PGE and PGF, in which the omega chain hasbeen modified with the common feature of containing a ring structure,for the treatment of glaucoma or ocular hypertension. The inventionrelates also to ophthalmic compositions, containing an active amount ofthese prostaglandin derivatives, and the manufacture of suchcompositions.

[0002] Glaucoma is an eye disorder characterized by increasedintraocular pressure, excavation of the optic nerve head and gradualloss of the visual field. An abnormally high intraocular pressure iscommonly known to be detrimental to the eye, and there are clearindications that, in glaucoma patients, this probably is the mostimportant factor causing degenerative changes in the retina. Thepathophysiological mechanism of open angle glaucoma is, however, stillunknown. Unless treated successfully glaucoma will lead to blindnesssooner or later, its course towards that stage is typically slow withprogressive loss of the vision.

[0003] The intraocular pressure, IOP (abbr. of intraocular pressure) canbe defined as according to the formula:

IOP=P _(e) +F×R  (1)

[0004] where P_(e) is the episcleral venous pressure, generally regardedas being around 9 mm Hg, F the flow of aqueous humor, and R theresistance to outflow of aqueous humor through the trabecular meshworkand adjacent tissue into Schlemm's canal.

[0005] Besides passing through Schlemm's, canal aqueous humor might alsopass through the ciliary muscle into the suprachoroidal space andfinally leave the eye through sclera. This uveoscleral route has beendescribed for instance by Bill (1975). The pressure gradient in thiscase is insignificant compared to the gradient over the interior wall ofSchlemm's canal and adjacent tissue in the former case. The flowlimiting step along the uveoscleral route is assumed to be the flow fromthe anterior chamber into the suprachoroidal space.

[0006] A more complete formula is given by:

IOP=P _(e)+(F _(t) −F _(u))×R  (2)

[0007] where P_(e) and R are defined as above, F_(t) is the totaloutflow of aqueous humor and F_(u) is the fraction passing via theuveoscleral route.

[0008] IOP in human beings is normally in the range of 12-22 mm Hg. Athigher values, for instance over 22 mm Hg, there is a risk that the eyemay be affected. In one particular form of glaucoma, low tensionglaucoma, damage may occur at intraocular pressure levels otherwiseregarded as physiologically normal. The reason for this could be thatthe eye in these individuals is unusually sensitive to pressure. Theopposite situation is also known, that some individuals may exhibit anabnormally high intraocular pressure without any manifest defects in thevisual field or optic nerve head. Such conditions are usually referredto as ocular hypertension.

[0009] Glaucoma treatments can be given by means of drugs, laser orsurgery. In drug treatment, the purpose is to lower either the flow (F)or the resistance (R) which, according to formula (1) above, will resultin a reduced IOP; alternatively to increase the flow via the uveoscleralroute which according to formula (2) also gives a reduced pressure.Cholinergic agonists, for instance pilocarpine, reduce the intraocularpressure mainly by increasing the outflow through Schlemm's canal.

[0010] Prostaglandins, which recently have met an increasing interest asIOP-lowering substances may be active in that they will cause anincrease in the uveoscleral outflow (Crawford et al, 1987, and Nilssonet al, 1987). They do not appear, however to have any effect on theformation of aqueous humor or on the conventional outflow throughSchlemm's canal (Crawford et al, 1987).

[0011] The use of prostaglandins and their derivatives is described forinstance in U.S. Pat. No. 4,599,353 and EP 87103714.9, and by Bito L Zet al (1983), Camras C B et al (1981, 1987a, 1987b, 1988), Giuffrè G(1985), Kaufman P L (1986), Kersetter J R et al (1988), Lee P -Y et al(1988) and Villumsen J et al (1989).

[0012] With respect to the practical usefulness of some of thepreviously described prostaglandins and derivatives, as suitable drugsfor treating glaucoma or ocular hypertension, a limiting factor is theirproperty of causing superficial irritation and vasodilation in theconjunctiva. It is probable, moreover, that prostaglandins have anirritant effect on the sensory nerves of the cornea. Thus local sideeffects will arise in the eye already when the amounts of prostaglandinadministered are quite small—that is, already when the doses are lowerthan those that would be desirable for achieving maximum pressurereduction. It has thus been found, for instance, that for this reason itis clinically impossible to use PGF_(2α)-1isopropyl ester in the amountthat would give maximum pressure reduction. Prostaglandins, beingnaturally occurring autacoids, are very potent pharmacologically andaffect both sensory nerves and smooth muscle of the blood vessels. Sincethe effects caused by administrations of PGF_(2α) and its esters to theeye, comprise in addition to pressure reduction also irritation andhyperemia (increased blood flow), the doses currently practicable inclinical tests are necessarily very low. The irritation experienced whenPGF_(2α) or its esters are applied, consists mainly in a feeling ofgrittiness or of having a foreign body in one's eye, this being usuallyaccompanied by increased lacrimation.

[0013] We have now found that a solution to the problems discussed aboveis the use of certain derivatives of prostaglandins A, B, D, E and F, inwhich the omega chain has been modified with the common feature ofcontaining a ring structure, for the treatment of glaucoma or ocularhypertension.

[0014] The prostaglandin derivatives have the general structure

[0015] wherein A represents the alicyclic ring C₈-C₁₂ and the bondsbetween the ring and the side chains represent the various isomers. InPGA, PGB, PGD, PGE and PGF A has the formula

[0016] The invention is based on the use of derivatives characterized bytheir omega chain and various modifications of the alpha chain istherefore possible still using the inventive concept. The alpha chaincould typically be the naturally occuring alpha chain, which isesterified to the structure

[0017] in which R₁ is an alkyl group, preferably with 1-10 carbon,especially 1-6 atoms, for instance metyl, ethyl, propyl, isopropyl,butyl, isobutyl, neopentyl or benzyl or a derivative giving the finalsubstance equivalent properties as a glaucoma agent. The chain couldpreferably be a C₆-C₁₀ chain which might be saturated or unsaturatedhaving one or more double bonds, and allenes, or a triple bond and thechain might contain one or more substituents such as alkyl groups,alicyclic rings, or aromatic rings with or without hetero atoms.

[0018] The omega chain is defined by the following formula:

[0019] wherein

[0020] C is a carbon atom (the number is indicated within parenthesis)

[0021] B is a single bond, a double bond or a triple bond

[0022] D is a chain with 1-10, preferably 2-8, and especially 2-5, andparticularly 3 carbon atoms, optionally interrupted by preferably notmore than two hetero atoms (O,S, or N), the substituent on each carbonatom being H, alkyl groups, preferably lower alkyl groups within 1-5carbon atoms, a carbonyl group, or a hydroxyl group, whereby thesubstituent on C₁₅ preferably being a carbonyl group, or (R)—OH or(S)—OH; each chain D containing preferably not more than three hydroxylgroups or not more than three carbonyl groups,

[0023] R₂ is a ring structure such as a phenyl group which isunsubstituted or has at least one substituent selected from C₁-C₅ alkylgroups, C₁-C₄ alkoxy groups, trifluoromethyl groups, C₁-C₃ aliphaticacylamino groups, nitro groups, halogen atoms, and phenyl group; or anaromatic heterocyclic group having 5-6 ring atoms, like thiazol,imidazole, pyrrolidine, thiophene and oxazole; or a cycloalkane or acycloalkene with 3-7 carbon atoms in the ring, optionally substitutedwith lower alkyl groups with 1-5 carbon atoms.

[0024] Some examples on derivatives which were evaluated are thefollowing (for structure information see Table I):

[0025] (1) 16-phenyl-17,18,19,20-tetranor-PGF_(2α)-isopropylester

[0026] (2) 17-phenyl-18,19,20-trinor-PGF_(2α)-isopropylester

[0027] (3) 15-dehydro-17-phenyl-18,19,20-trinor-PGF_(2α)-isopropylester

[0028] (4) 16-phenoxy-17,18,19,20-tetranor-PGF_(2α)-isopropylester

[0029] (5) 17-phenyl-18,19,20-trinor-PGE₂-isopropylester

[0030] (6) 13,14-dihydro-17-phenyl-18,19,20-trinor-PGA₂-isopropylester

[0031] (7) 15-(R)-17-phenyl-18,19,20-trinor-PGF_(2α)-isopropylester

[0032] (8)16-[4-(methoxy)-phenyl]-17,18,19,20-tetranor-PGF_(2α)-isopropylester

[0033] (9)13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α)-isopropylester

[0034] (10) 18-phenyl-19,20-dinor-PGF_(2α)-isopropylester

[0035] (20) 19-phenyl-20-nor-PGF_(2α)-isopropylester

[0036] The most preferred derivatives at present are those in which theomega chain of the prostaglandin has the 18,19,20-trinor form, andespecially the 17-phenyl analogs, such as the 15-(R)-, 15-dehydro and13,14-dihydro-17-phenyl-18,19,20-trinor forms. Such derivatives arerepresented by (3), (6), (7) and (9) in the formulas given in Table I.

[0037] In the formula given above the most preferred structure atpresent is accordingly obtained when the prostaglandin is a derivativeof PGA, PGD, PGE or PGF, especially of PGA₂, PGD₂, PGE₂ and PGF_(2α)

[0038] B is a single bond or a double bond

[0039] D is a carbon chain with 2-5, especially 3 atoms; C₁₅ having acarbonyl or (S)—OH substituent and C₁₆-C₁₉ having lower alkylsubstituents, or preferably H

[0040] R₂ is a phenyl ring optionally having substituents selected amongalkyl and alkoxy groups.

[0041] The invention thus relates to the use of certain derivatives ofPGA, PGB, PGD, PGE and PGF for the treatment of glaucoma or ocularhypertension. Among these derivatives defined above it has been foundthat some are irritating or otherwise not optimal, and in certain casesnot even useful due to adverse effects and these are excluded in thatthe group of prostaglandin derivatives defined above is limited totherapeutically effective and physiologically acceptable derivatives. Sois for instance (1) 16-phenyl-17,18,19,20-tetranor-PGF_(2α)-isopropylester irritating while this can be eliminated by substituting the phenylring with a methoxy group giving formula (8) which represents atherapeutically more useful compound,

[0042] The method for treating glaucoma or ocular hypertension consistsin contacting an effective intraocular pressure reducing amount of acomposition, as aforesaid, with the eye in order to reduce the eyepessure and to maintain said pressure on a reduced level. Thecomposition contains 0.1-30 μg, especially 1-10 μg, per application ofthe active substance i.e. a therapeutically active and physiologicallyacceptable derivative from the group defined above; the treatment mayadvantageously be carried out in that one drop of the composition,corresponding to about 30 μl, is administered about 1 to 2 times per dayto the patient's eye. This therapy is applicable both to human beingsand to animals.

[0043] The invention further relates to the use of therapeuticallyactive and physiologically acceptable prostaglandin derivatives from thegroup defined above for the preparation of an ophthalmologicalcomposition for the treatment of glaucoma or ocular hypertension.

[0044] The prostaglandin derivative is mixed with an ophthalmologicallycompatible vehicle known per se. The vehicle which may be employed forpreparing compositions of this invention comprises aqueous solutions ase.g. physiological salines, oil solutions or ointments. The vehiclefurthermore may contain ophthalmologically compatible preservatives suchas e.g. benzalkonium chloride, surfactants like e.g. polysorbate 80,liposomes or polymers, for example methyl cellulose, polyvinyl alcohol,polyvinyl pyrrolidone and hyaluronic acid; these may be used forincreasing the viscosity. Furthermore, it is also possible to usesoluble or insoluble drug inserts when the drug is to be administered.

[0045] The invention is also related to ophthalmological compositionsfor topical treatment of glaucoma or ocular hypertension which comprise.an effective intra ocular pressure reducing amount of a prostaglandinderivative as defined above and an ophthalmologically compatiblecarrier, the effective amount comprising a dose of about 0.1-30μ inabout 10-50μ of the composition.

[0046] In the experiments carried out in this investigation the activecompound, in an amount, varying with potency of the drug, from 30 μg to300 μg/ml was dissolved in a sterilized aqueous solution (saline 0.9%)containing 0.5% polysorbate-80 as solubilizing agent.

[0047] The invention is illustrated by means of the followingnon-limitative examples.

[0048] Synthesis of Prostaglandin Derivatives

EXAMPLE 1 Preparation of 16-phenyl-17,18,19,20-tetranorPGF_(2α)-isopropyl Ester (1)

[0049] A 50 ml round bottom flask equipped with a magnetic stirring barwas charged with 17.5 mg (0.04 mmol) 16-phenyl-17,18,19,20-tetranorPGF_(2α) (Cayman Chemical), 5 ml CH₂Cl₂,30.2 mg (0.23 mmol)diisopropylethylamine. This solution was stirred at −10° C. and 13.5 mg(0.07 mmol) of isopropyltriflate (freshly prepared) was added. Thissolution was allowed to stand at −10° C. for 15 min and was then slowlywarmed to room temperature. When the esterification was completeaccording to TLC (usually after 3-4 h at room temperature) the solventwas removed in vacuo. The residue was diluted with 20 ml ethylacetate,washed with 2×10 ml 5% sodium hydrogencarbonate and 2×10 ml 3% citricacid. The organic layer was dried over unhydrous sodium sulfate. Thesolvent was removed in vacuo and the residue was purified by columnchromatography on silica gel-60 using ethyl acetate: aceton 2:1 aseluent. The title compound was obtained as a colourless oily substance(71% yield).

[0050] Nuclear Magnetic Resonance Spectrum (CDCl₃)-ppm: δ 1.2 (6H d) 3.3(1H q) 2.85 (2H d) 5.0 (1H m) 3.85 (1H m) 5.3-5.7 (4H m) 4.15 (1H t)7.15-7.35 (5H m)

EXAMPLE 2 Preparation of 17-phenyl-18,19,20-trinor PGF_(2α)-isopropylEster (2)

[0051] A 50 ml round bottom flask equipped with a magnetic stirring barwas charged whith 20 mg (0.05 mmol) 17-phenyl-18,19,20-trinor PGF_(2α)(Cayman Chemicals), 6 ml acetone, 39.2 mg (0.25 mmol) DBU and 42.5 mg(0.25 mmol) isopropyl iodide. The solution was allowed to stand at roomtemperature for 24 h, the solvent was removed in vacuo and the residuewas diluted with 30 ml of ethyl acetate, washed twice with 10 ml 5%sodiumhydrogen carbonate and 10 ml 3% citric acid. The solvent wasremoved in vacuo, and the crude product was chromatographed on silicagel-60 using ethyl acetate: acetone 2:1 as eluent. The title compound(2) was obtained as an oily substance (65% yield).

[0052] Nuclear Magnetic Resonance Spectrum (CDCl₃)-ppm: δ 1.2 (6 m) 4.9(1H m) 3.9 (1H m) 5.4-5.6 (4H m) 4.1 (1H t) 7.1-7.3 (5H m) 4.2 (1H m)

EXAMPLE 3 Preparation of 15-dehydro-17-phenyl-18,19,20-trinorPGF_(2α)-isopropyl Ester (3)

[0053] 20.9 mg (0.092 mmol) DDQ was added to a solution of 10 mg (0.023mmol) 17-phenyl-18,19,20 trinor PGF_(2α)-isopropyl ester (2) in 8 mldioxane. The reaction mixture immediately turned brown, the reactionmixture was stirred at room temperature for 24 h. The precipitate formedwas filtered, washed with 10 ml ethyl acetate, the filtrate was dilutedwith 10 ml ethylacetate washed with 2×10 ml water, 2×10 ml NaOH IM and20 ml brine. The organic layer was dried on unhydrous sodium sulfate andthe solvent was removed in vacuo, the residue was purified by columnchromatography on silica gel using ethyl acetate: ether 1:1 as eluent.The title compound (3) was obtained as a colourless oily substance (76%yield).

[0054] Nuclear Magnetic Resonance Spectrum (CDCl₃),-ppm: δ 1.2 (6H d)5.4 (2H m) 4.0 (1H m) 6.2 (1H d) 4.2 (1H m) 6.7 (1H q) 5.0 (1H m)7.15-7.35 (5H m)

EXAMPLE 4 Preparation of 16-phenoxy-17,18,19,20-tetranorPGF_(2α)-isopropyl Ester(4)

[0055] Following a procedure similar to that described in example 2using 20 mg (0.051 mmol) 16-phenoxy-17,18,19,20-tetranor PGF_(2α)(Cayman Chemicals). The title compound (4) was an oily substance (53.2%yield).

[0056] Nuclear Magnetic Resonance Spectrum (CDCl₃)-ppm: δ 1.2 (6H d) 5.4(2H m) 3.9 (3H m) 5.7 (2H m) 4.2 (1H m) 6.9 (3H m) 4.5 (1H m) 7.3 (2H m)5.0 (1H m)

EXAMPLE 5 Preparation of 17-phenyl-18,19,20-trinor PGE₂-isopropyl Ester(5)

[0057] Following a procedure similar to that described in example 2using 10 mg (0.026 mmol) 17-phenyl-18,19,20-trinor PGE₂ (CaymanChemicals). The crude product was purified by column chromatography onsilica gel-60 using ether as eluent. The title compound (5) was an oilysubstance (38.9% yield).

[0058] Nuclear Magnetic Resonance Spectrum (CDCl₃)-ppm: δ 1.2 (6H d) 5.3(2H m) 3.9-4.1 (2H m) 5.6 (2H m) 4.9 (1H m) 7.2 (5H m)

EXAMPLE 6 Preparation of 13,14-dihydro-17-phenyl-18,19,20-trinorPGA₂-isopropyl Ester (6)

[0059] Following a procedure similar to that described in example 2using 10 mg (0.026 mmol) 13,14-dihydro-17-phenyl PGA₂ (CaymanChemicals). The crude product was chromatographed on silica gel-60 usingether as eluent.

[0060] Nuclear Magnetic Resonance Spectrum (CDCl₃)-ppm: δ 1.2 (6H d) 5.4(2H m) 4.35 (1H m) 7.3 (5H m) 5.0 (1H m)

EXAMPLE 7 Preparation of 15-(R)-17-phenyl-18,19,20-trinorPGF_(2α)-isopropyl Ester (7). (Table II)

[0061] 7.1 Preparation of1-(S)-2-oxa-3-oxo-6-(R)-(3-oxo-5-phenyl-1-trans-pentenyl)-7-(R)-(4-phenylbenzoyloxy)-cis-bicyclo[3,3,0] Octane (13).

[0062] 18 g (0.05 mol) alcohol (11), 32 g (0.15 mol) DCC, 39.1 g (0.5mol) DMSO (newly distilled from CaH₂) and 30 ml DME were charged to a200 ml flask under nitrogen. Ortho-phosphoric acid was added in oneportion, and an exothermic reaction occured. The reaction mixture wasstirred mechanically at room temperature for 2 h, and the resultantprecipitate was filtered and washed with DME. The filtrate (12) can beused directly for Emmon condensation reaction.

[0063] To a suspension of 1.2 g (0.04 mol) NaH (80% washed withn-pentane to remove mineral oil) in 100 ml DME under nitrogen was addeddropwise 12.3 g (0.048) dimethyl-2-oxo-4-phenyl-butyl-phosphonate in 30ml DME. The mixture was stirred mechanically for 1 h at roomtemperature, then cooled to −10° C. and a solution of the crude aldehyde(12) was added in dropwise. After 15 min at 0° C. and 1 h at roomtemperature the reaction mixture was neutralized with glacial aceticacid, the solvent was removed under vaccum, and to the residue was added100 ml ethyl acetate, washed with 50 ml water and 50 ml brine. Theorganic layer was dried over unhydrous sodium sulfate. The solvent wasremoved in vacuo and the resulting white precipitate filtered and washedwith cold ether. The title compound (13) was obtained as a crystallinesubstance mp 134.5-135.5 (53% yield).

[0064] 7.2 Preparation of1-(S)-2-oxa-3oxo-6-(R)-[3-(R,S)-hydroxy-4-phenyl-1-trans-pentenyl]-7-(R)-(4-phenylbenzoyloxy)cis-bicyclo [3,3,0]Octane (14).

[0065] 10 g (0.021 mol) enone (13) and 3.1 g (0,008 mol) cerous-chlorideheptahydrate in 50 ml methanol and 20 ml CH₂Cl₂ were charged to a 200 mlround bottom flask equipped with a magnetic stirring bar and was cooledto −78° C. under nitrogen. Sodium borohydride was added in smallportions, after 30 min the reaction mixture was quenched by addition ofsaturuted NH₄Cl, and extracted with 2×50 ml ethyl acetate. The extractswere dried and concentrated to leave a colourless oil (98% yield).

[0066] 7.3 Preparation of1-(S)-2-oxa-3-oxo-6-(R)-[3-(R,S)-hydroxy-4-phenyl-1-trans-pentenyl]-7-(R)-hydroxy-cis-bicyclo-[3,3,0]Octane (15).

[0067] To a solution of 9.8 g (0.02 mol) ketal (14) in 100 ml absolutemethanol was added 1.7 (0.012 mol) potassium carbonate. The mixture wasstirred with a magnetic bar, at room temperature after 3 h. The mixturewas neutralized with 40 ml HCl 1 M, and extracted with 2×50 ml ethylacetate. The extracts were then dried on unhydrous sodium sulfate andconcentrated. The crude product was chromatographed on silica gel usingethyl acetate: acetone as eluent. The title compound (15) was obtainedas an oily substance (85% yield).

[0068] 7.4 Preparation of1-(S)-2-oxa-3-hydroxy-6-(R)-[3-(R,S)-hydroxy-4-phenyl-1-trans-pentenyl]-7-(R)-hydroxy-cis-bicyclo[3,3,0](16).

[0069] To a solution of 3 g(0.011 mol) lactone (15) in 60 ml unhydrousTHF, stirred magnetically and cooled to −78° C., 4.5 g (0.0315 mol)DIBAL-H in toluene was added dropwise. After 2 h the reaction mixturewas quenched by addition of 75 ml methanol. The mixture was filtered,the filtrate was concentrated in vacuo and the residue waschromatographed on silica gel-60 using ethyl acetate: acetone 1:1 aseluent. The title compound (16) was obtained as a semisolid substance(78% yield).

[0070] 7.5 Preparation of 15-(R,S)-17-phenyl-18,19,20-trinorPGF_(2α)(17).

[0071] 2.5 g (25 mmol) sodium methyl sulfinylmethide in DMSO (freshlyprepared from sodium anhydride and DMSO) was added dropwise to asolution of 5.6 g (12.6 mmol) 4-caboxybutyl triphenyl-phosphoniumbromide in 12 ml DMSO. To the resultant red solution of the ylide wasadded dropwise a solution of the 1.2 g (4.2 mmol) hemiacetal (16) in 13ml DMSO, and the mixture was stirred for 1 h. The reaction mixture wasdiluted with 10 g ice and 10 ml water and extracted with 2×50 ml ethylacetate, whereafter the aqueous layer was cooled, acidified with HCl 1 Mand extracted with ethyl acetate, and then the organic layer was driedand concentrated. The resulting crude product was a colourlesssubstance. The purity of the title compound (17) was estimated by TLC onsilica gel using ethyl acetate: acetone: acetic acid 1:1:0.2 v/v/v aseluent.

[0072] 7.6 Preparation of 15-(R)-17-phenyl-18,19,20-trinorPGF_(2α)-isopropyl Ester (7).

[0073] The crude product (17) was esterified following a proceduresimilar to that described in example 2 the product was purified bycolumn chromatography on silica gel-60 using ethyl acetate as eluent andthe resulting mixture of C₁₅ epimeric alcohol were separated.

[0074] The title compound (7) was obtained as a colourless oilysubstance (46% yield).

[0075] Nuclear Magnetic Resonance Spectrum (CDCl₃),-ppm: δ 1.2 (6H m)5.4 (2H m) 3.9 (1H m) 5.6 (2H m) 4.15 (2H m) 7.2 (5H m) 4.95 (1H m)

EXAMPLE 8 Preparation of 16-[4-(methoxy)phenyl]-17,18,19,20-tetranorPGF_(2α)-isopropyl Ester (8)

[0076] Following a procedure similar to that described in example 7 withmodified step 7-2, the aldehyde 12 described in step 7-2 was reactedwith dimethyl-2-oxo-3-[4-(methoxy)phenyl]-propylphosphonate and waspurified by column chromatography on silica gel-60 using ethyl acetate:toluene 1:1 as eluent. A colourless oily substance was obtained (57%yield).

[0077] The title compound 16-[4-(methoxy)phenyl]-17,18,19,20-tetranorPGF_(2α)-isopropyl ester (8) was obtained as an oily substance, andpurified by column chromatography on silica gel-60 using ethyl acetateas eluent (46% yield).

[0078] Nuclear Magnetic Resonance Spectrum (CDCl₃)-ppm: δ 1.2 (6H d) 5.0(1H m) 2.8 (2H d) 5.4 (2H m) 3.75 (3H S) 5.6 (2H m) 3.9 (1H m) 6.8 (2Hd) 4.15 (1H m) 7.2 (2H d) 4.3 (1H m)

EXAMPLE 9 Preparation of 13,14-dihydro-17-phenyl-18,19,20-trinorPGF_(2α)-isopropyl Ester (9)

[0079] Following a procedure similar to that described in example 7,with minor modification, 5 g (0.018 mol) enone (13) in 100 ml THF wasreduced using 2.03 g 10% pd/c under hydrogen atmosphere. Aftercompletion of the reaction (as determined by TLC on silica gel usingethylacetate: toluene 1:1 as eluent) the mixture was filtered on celite.The filtrate was concentrated in vacuo and an oily substance wasobtained (86% yield).

[0080] The final product 13,14-dihydro-17-phenyl-18,19,20-trinorPGF_(2α)-isopropyl ester containing a mixture of C₁₅ epimeric alcoholswere separated by preparative liquid chromatography using 40% CH₃CN inwater v/v as eluent.

[0081] Nuclear Magnetic Renonance Spectrum (CDCl₃)-ppm: δ 1.2 (6H d) 5.0(1H m) 3.6 (1H m) 5.4 (2H m) 3.9 (1H m) 7.2 (5H m) 4.15 (1H m)

EXAMPLE 10 Preparation of 18-phenyl-19,20-trinor PGF_(2α)-isopropylEster (10)

[0082] Following a procedure similar to that described in example (7)with modified step 7-2. The aldehyde (12) described in 7-2 was reactedwith dimethyl-2-oxo-5-phenyl pentyl phosphonate gave a crystallinesubstance trans-enone lactone (67% yield).

[0083] The final product 18-phenyl-19,20-dinor PGF_(2α)-isopropyl ester(10) was purified by column chromatography on silica gel-60 using ethylacetate as eluent gave a colourless oil (41% yield). 1.2 (6H d) 5.0 (1Hm) 3.95 (1H m) 5.4 (2H m) 4.10 (1H m) 5.6 (2H q) 4.20 (1H m) 7.2 (5H m)

EXAMPLE 11 Preparation of 19-phenyl-20-nor-PGF_(2α)-isopropyl Ester (20)

[0084] Following a procedure similar to that described in example (7)with modified step (7-2).

[0085] The aldehyde (12) described in (7-2) was reacted withdimethyl-2-oxo-6-phenyl-hexylphosphonate gave a colourless oiltrans-enone lactone (56% yield).

[0086] The final product 19-phenyl-20-nor-PGF_(2α)-isopropyl ester (20)was a colourless oil, and was purified by column chromatography onsilica gel-60 using ethyl acetate as eluent (30% yield).

[0087] Nuclear Magnetic Resonance Spectrum (CDCl₃)-ppm: δ 1.2 (6H d) 5.0(1H m) 2.6 (2H t) 5.4 (2H m) 3.9 (1H m) 5.5 (2H t) 4.1 (1H m) 7.2 (5H m)4.2 (1H m)

[0088] Studies of Eye Pressure Lowering Effect and Adverse Reactions

[0089] The intraocular pressure (IOP) was determined in animals with apneumatonometer (Digilab Modular One™, Bio Rad), specially calibratedfor the eye of the particular species. The cornea was anaesthetized with1-2 drops of oxibuprocain before each IOP measurement. In healthy humanvolunteers IOP was measured with applanation tonometry or with an airpuff tonometer (Keeler pulsair). For applanation tonometry either apneumatonometer (Digilab) or Goldmann's applanation tonometer mounted ona slit lamp microscope was used. The cornea was anaesthetized withoxibuprocain before each measurement with applanation tonometry. Nolocal anaesthesia was employed before measurement with the pulsairtonometer.

[0090] The ocular discomfort after application of the test substanceswas evaluated in cats. The behaviour of cats

[0091] after topical application of the test drug was followed andocular discomfort was graded on a scale from 0 to 3, 0 indicatingcomplete absence of any signs of discomfort, and 3 indicating maximalirritation as obvious from complete lid closure.

[0092] Conjunctival hyperemia after topical application of the testsubstances was evaluated in rabbits. The conjunctiva at the insertion ofthe superior rectus muscle of the eye was inspected or photographed withregular intervals and the degree of hyperemia was later evaluated fromthe color photographs in a blind manner. Conjunctival hyperemia wasevaluated on a scale from 0 to 4, 0 indicating complete absence of anyhyperemia, and 4 indicating marked hyperemia with conjunctival chemosis.

[0093] For determination of the effects on the intraocular pressure,primarily monkeys (cynomolgus) were employed. The reason for this isthat the monkey eye is highly reminiscent of the human eye and therefor,generally, drug effects are readily extrapolated to the human eye.However, the disadvantage of using the monkey eye as a model is that theconjunctiva in this species is pigmented making it impossible toevaluate conjunctival hyperemia and furthermore, the monkey eye isrelatively insensitive to irritation. Therefore, the cat eye, being verysensitive to prostaglandins was used for evaluating ocular discomfortand the rabbit eye with pronounced tendency to hyperemic reactions wasused for evaluating conjunctival and episcleral hyperemia.

[0094] It is evident from Table III that modification of the omega chainof the prostaglandin skeleton introduced new and unexpected features tothe prostaglandins with respect to ocular irritation (discomfort).Particularly 17-phenyl,18,19,20-trinor-PGF_(2α)-IE and analogs wereunique in exhibiting a complete loss of ocular irritation with retainedIOP lowering effect in monkeys. Whereas the17-phenyl,18,19,20-trinor-PGF_(2α) derivatives were extremely welltolerated, 16-phenyl-17,18,19,20-tetranor-PGF_(2α)-IE caused clearocular discomfort although to a lesser degree than PGF_(2α)-IE or15-propionate-PGE₂-IE (Table III). However, substituting a hydrogen atomin the phenyl ring with a methoxy group having electron donatingproperties rendered the molecule practically free of ocular irritatingeffect, Table III. It is also evident from Table III that18-phenyl-19,20,-dinor-PGF_(2α)IE, 19-phenyl-20-nor-PGF_(2α)-IE as wellas 17-phenyl-18,19,20-trinor-PGE₂-IE and13,14-dihydro-17-phenyl-18,19,20-trinor-PGA₂-IE, had no or very littleirritating effect in the eye of cats. This indicates that the inventionnot only is valid for 16-, and 17-tetra- and trinor analogs of PGF_(2α)but for a range of omega chain modified and ring substituted analogs ofPGF_(2α) (as exemplified with 16-phenyl-17,18,19,20-tetranor-PGF_(2α)-IEto 19-phenyl-20-nor-PGF_(2α)-IE), and more importantly even fordifferent members of the prostaglandin family such as PGE₂ and PGA₂modified in an analogous way (Table III). Thus, modifying the omegachain and substituting a carbon atom in the chain with a ring structureintroduces completely new, unexpected and advantageous qualities tonaturally occuring prostaglandins in that the irritating effect in theconjunctiva and cornea is abolished. In the case of16-phenyl-17,18,19,20-tetranor-PGF_(2α)-IE exhibiting some irritatingeffect substituting a hydrogen atom in the ring structure with e.g. amethoxy group attenuates or abolishes the irritating effect.

[0095] In addition to the lack of ocular discomfort the omega chainmodified analogs also exhibited an advantage over naturally occuringprostalgandins in that they caused considerably less conjunctivalhyperemia as studied in the rabbit eye (Table IV). Particularly,15-dehydro-17-phenyl-18,19,20-trinor-PGF_(2α)-IE,13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α)-IE,and 13,14-dihydro-17-phenyl-18,19,20-trinor PGA₂-IE were advantageous inthis respect. Also 18-phenyl-19,20-dinor-PGF_(2α)-IE and19-Phenyl-20-nor-PGF_(2α)-IE induced very little conjunctival hyperemia(TableIV).

[0096] The intraocular pressure lowering effect of omega chain modifiedand ring-substituted prostaglandin analogs is demonstrated in Table V.It can be seen that particularly 16-phenyl-tetranor and 17-phenyl-trinorprostaglandin analogs significantly reduced IOP in animal eyes (TableV). In all but two series of experiments cynomolgus monkeys were used.It is of particular interest to note that 17-phenyl-18,19,20-trinorPGF_(2α)-derivatives exhibiting no ocular irritation and only modestconjunctival/episcleral hyperemia significantly lowered IOP in primates.It should furthermore be observed that both16-phenyl-17,18,19,20-tetranor-PGF_(α)-IE,18-phenyl-19,20-dinor-PGF_(2α)-IE and 19-phenyl-20-nor-PGF_(α)-IEreduced the intraocular pressure, thus, modification of the omega chainand substituting a carbon atom in the chain with a ring structure do notrender the molecule inactive with respect to the effect on theintraocular pressure. Furthermore, it should be observed thatsubstituting a hydrogen on the ring structure of16-phenyl,17,18,19,20-tetranor-PGF_(2α)-IE with a methoxy groupeliminated much of the ocular irritating effect preserving most of theintraocular pressure lowering effect. Thus, omega chain modified andring substituted prostaglandin analogs reduce IOP effectively inanimals. It is further demonstrated in Table V that16-phenoxy-17,18,19,10-tetranor-PGF_(2α)-IE effectively lowers theintraocular pressure as studied in cats. Thus, substituting carbon 17 inthe omega chain with a hetero atom, in this case oxygen, does not renderthe molecule inactive with respect to the effect on IOP.

[0097] It is noteworthy that most of the17-phenyl,18,19,20-trinor-prostaglandin analogs had poor intraocularpressure lowering effect in cats, even at high doses. It is to beobserved that the doses at which compounds were used presented in TableIII are lower than those e.g. in Table V. Doses presented in Table IIIshould be explicitly compared with those of the naturally occuringprostaglandins in the same table. The same is true for Table IV. It isclear that with increasing dose side effects may increase. However, thedoses of prostaglandin derivatives used in monkeys are comparativelysimilar to those used in human volunteers, (Table VI) being practicallyfree of side effects.

[0098] The effect of some omega chain modified prostaglandin analogs,more specifically 17-phenyl-18,19,20-trinor-PGF_(2α)-IE,15-dehydro-17-phenyl-18,19,20-trinor-PGF_(2α)-IE,15-(R)-17-phenyl-18,19,20-trinor-PGF_(2α)-IE,13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α)-IE, and18-phenyl-19-20-dinor-PGF_(2α)-IE on the intraocular pressure of healthyhuman volunteers is demonstrated in Table VI. All compoundssignificantly reduced the intraocular pressure. It is particularlysignificant in this respect that none of the compounds had anysignificant irritating effect (ocular discomfort) and that13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α)-IE and15-dehydro-17-phenyl-18,19,20-trinor-PGF_(2α)-IE caused very little ifany conjunctival/episcleral hyperemia in man.

[0099] Thus, omega chain modified, and ring substituted prostaglandinanalogs seem to be unique in that these compounds reduce IOP withoutcausing significant ocular side effects such as hyperemia anddiscomfort.

[0100] The present invention thus describes a group of compoundsexhibiting the unique property of causing insignificant ocular sideeffects while retaining the intraocular pressure lowering effect. Fromthe foregoing it is evident that the crucial modification of themolecule is a ring structure in the omega chain. Furthermore,substituents in the ring structure and/or in the omega chain may beintroduced in certain molecules still exhibiting some side-effects inthe eye. Hetero atoms may also be introduced into the ring substitutedomega chain. Presently, particularly17-phenyl-18,19,20-trinor-PGF_(2α)-derivatives seem very promising fortherapeutic use in glaucoma. From the scientific literature it isevident that PGE₂ and PGA₂ or their esters lower IOP in the monkey (seeBito et al, 1989). Clinical studies with PGE₂ have also been performeddemonstrating IOP-lowering effect in man (Flach and Eliason (1988)).Thus, the analogy with PGF_(2α) and its esters lowering IOP in theprimate eye is logic. It is most reasonable to assume that otherprostaglandins with modified omega chain exhibit essentially the sameproperties as PGF_(2α) with modified omega chain, i.e. IOP loweringeffect without side effects. TABLE I

[0101] TABLE II

Reagents: a) DCC/DMSO/DME b) NaH/dimethyl-2-oxo-4-phenylbutylphosphonate/DME c) CeCl₃.7H₂O/NaBH₄/CH⁻ ₃OH/−78° C. d) K₂CO₃/CH₃OH e)Dibal/−78° C. f) NaCH₂SOCH₃/(4-carboxybutyl)-triphenylphosphoniumbromide/DMSO g) DBU/iprI/acetone

[0102] TABLE III Irritative effect of naturally occuring prosta-glandins (PGF_(2α), PGD₂ and PGE₂), and omega chain modified analogsapplied as isopropylester on the cat eye. The avarage degree ofdiscomfort was evaluated during 60 min after topical application of therespective test drug. The numbers within paranthesis refer to Table I.Dose Degree of Substance (pg) occular irritation PGF_(2α)-isopropylester(-IE) 1 3.0 ± 0.0 15-propionate-PGE₂-IE 0.1-1   3.0 ± 0.015-propionate-PGD₂-IE 1 1.3 ± 0.2 17-phenyl-18,19,20- (2) 1-5 0trinor-PGF_(2α)-IE 15-dehydro-17-phenyl- (3) 5 0 18,19,20-trinor-15-(R)-17-phenyl- 18,19,20-trinor-PGF_(2α)-IE (7) 1-5 013,14-dihydro-17-phenyl- (9) 1 0 16,19,20-trinor-PGF_(2α)-IE17-phenyl-18,19,20- (5) 0.3   0 trinor-PGE₂-IE 13,14-dihydro-17-phenyl-(6) 1 0 18,19,20-trinor-pGA₂-IE 16-phenyl-17,18,19,20- (1) 1 2.2 ± 0.3tetranor-PGF_(2α)-IE 16-[4-(methoxy)-phenyl]- (8) 1 0.2 ± 0.117,18,19,20-tetranor- PGF_(2α)-IE 18-phenyl-19,20-dinor- (10)  1 0.7 ±0.1 PGF_(2α)-IE 19-phenyl-20-nor-pGF_(2α)-IE (20)  1 0.5 ± 0.116-phenoxy-17,18,19,20- (4) 5 0.3 ± 0.2 tetranor-PGF_(2α)-IE

[0103] TABLE IV Degree of conjunctival hyperemia in the rabbit eye afterapplication of naturally occuring prostaglandins (PGF_(2α), and PGE₂),and omega chain modified analogs applied as isopropylesters. Dose Degreeof Substance (μg) hyperemia PGF_(2α)-isopropylester (-IE) 0.1 2.8 ± 0.215-propionate-PGE₂-IE 0.5 2.7 ± 0.3 16-phenyl-17,18,19,20- (1) 0.5 1.3 ±0.9 tetranor-PGF_(2α)-IE 17-phenyl-18,19,20-trinor- (2) 0.5 2.0 ± 0.3PGF_(2α)-IE 15-dehydro-17-phenyl- (3) 0.5 0.7 ± 0.318,19,20-trinor-PGF_(2α)-IE 15-(R)-17-phenyl-18,19,20- (7) 0.5 2.0 ± 0.0trinor-PGF_(2α)-IE 13,14-dihydro-17-phenyl- (9) 0.5 1.3 ± 0.318,19,20-trinor-PGF_(2α)-IE 17-phenyl-18,19,20-trinor- (5) 0.5 2.7 ± 0.2PGE₂-IE 13,14-dihydro-17-phenyl- (6) 0.5 0.3 ± 0.318,19,20-trinor-PGA₂-IE 18-phenyl-19,20-dinor- (10)  0.5 0.3 ± 0.2PGF_(2α)-IE 19-phenyl-20-nor-PGF_(2α)-IE (20)  0.5 0.2 ± 0.216-phenoxy-17,18,19,20- (4) 0.5 2.3 ± 0.3 tetranor-PGF_(2α)-IE

[0104] TABLE V Intraocular pressure reducing effect of naturallyoccuring prostaglandin (PGF_(2α)) and omega chain modified analogs asdetermined in cynomolgus monkeys or cats. Unless specified data wereobtained in monkeys. The figures within parenthesis refer to formulasgiven in Table I. Time after administration (hour) 0 1-2 3-4 6 SubstanceDose (μg) (mmHg) (mmHg) (mmHg) (mmHg) E 11.4 ± 0.7  8.3 ± 0.5  8.0 ± 0.6 9.3 ± 0.8 * * PGF_(2α)-isopropylester (IE)  1.5 C 11.0 ± 0.7 10.7 ± 0.410.1 ± 0.4 10.6 ± 0.9 16-phenyl-17, 18, 19, 20-  3.2 E 12.7 ± 1.1 11.8 ±1.1  9.1 ± 0.8  8.4 ± 0.7 * * tetranor-PGF_(2α)-IE (1) C 12.8 ± 0.5 14.0± 0.2 13.0 ± 0.8 11.7 ± 0.8 17-phenyl-18, 19, 20-  3.2 E 12.8 ± 0.6 11.9± 0.5  8.6 ± 0.3  9.5 ± 0.7 * trinor-PGF_(2α)-IE (2) C 13.4 ± 0.6 11.7 ±0.6 12.4 ± 0.2 11.9 ± 0.7 13, 14-dihydro-17—phenyl- 10.4 E 11.1 ± 0.9 8.3 ± 0.6  6.9 ± 0.4  7.7 ± 0.8 * 18, 19, 20-trinor-PGF_(2α)-IE (9) C10.6 ± 0.7  8.8 ± 0.9 10.3 ± 1.1  9.5 ± 1.0 18-phenyl-19, 20-donor-  3.1E  9.7 ± 0.9  9.6 ± 1.1  9.6 ± 1.1  8.8 ± 0.9 * PGF_(2α)-IE (10) C 10.1± 1.0  9.4 ± 1.2  9.8 ± 1.2  9.4 ± 0.9 16-phenoxy-17, 18, 19, 20  5 ** E20.5 ± 1.2 25.7 ± 1.2 19.2 ± 1.8 15.0 ± 1.2 * tetranor-PGF_(2α)-IE (4) C20.7 ± 1.2 22.7 ± 1.1 19.5 ± 0.9 19.2 ± 0.8 16-[4-(methoxy)-phenyl]- 3.2 E 11.2 ± 0.9 10.5 ± 1.3 9.8 ± 1.4  9.2 ± 0.9 17, 18, 19,20-tetranor- * PGF_(2α)-IE (8) C 10.4 ± 1.1 10.9 ± 1.0 11.3 ± 1.4  9.2 ±0.6 19-phenyl-20-nor-  1 ** E 16.9 ± 1.0 16.6 ± 0.7 15.8 ± 0.8 18.1 ±1.2 * PGF_(2α)-IE (20) C 17.1 ± 0.4 18.1 ± 0.6 18.9 ± 0.6 19.2 ± 0.8

[0105] TABLE VI Intraocular pressure reducing effect of different omegachain modified and ring substituted PGF_(2α)-IE analogs, in healthyhuman volunteers. The substance number is given within paranthesis. Timeafter administration (hours) Dose 0 4 6 8 Substance (μg) n Eye (mmHg)(mmHg) (mmHg) (mmHg) 17-phenyl-18, 19, 20-trinor- 1 4 Exp 11.9 ± 1.711.0 ± 0.9 10.1 ± 0.7  9.8 ± 0.7 PGF_(2α)-isop * * * ropylester (IE) (2)Contr 12.7 ± 1.7 13.9 ± 0.7 13.5 ± 1.2 12.5 ± 0.7 15-(R)-17-phenyl-18,19, 20- 10 3 Exp 12.9 ± 0.9 11.8 ± 0.6 11.0 ± 0.3 11.2 ± 1.3 *trinor-PGF_(2α)-IE (7) Contr 13.2 ± 1.4 13.7 ± 0.9 13.8 ± 1.0 15.1 ± 1.315-dehydro-17-phenyl- 10 4 Exp 17.7 ± 0.6 14.6 ± 0.2 13.6 ± 0.7 — * *18, 19, 20-trinor-PGF_(2α)IE (3) Contr 17.5 ± 0.7 16.4 ± 0.5 16.3 ± 1.0— 13, 14-dihydro-l7-phenyl- 1 4 Exp 14.2 ± 0.5 13.3 ± 1.1 12.2 ± 0.412.5 ± 0.9 * 18, 19, 20-trinor-PGF_(2α)IE (9) Contr 13.5 ± 0.6 14.2 ±1.2 15.2 ± 1.0 15.1 ± 0.7 18-phenyl-19, 20-dinor- 5 3 Exp 14.4 ± 1.012.2 ± 1.1 12.4 ± 1.2 11.9 ± 0.7 * PGF_(2α)-IE (10) Contr 15.2 ± 0.113.7 ± 1.2 14.4 ± 0.2 13.2 ± 0.5

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1. Use of a therapeutically active and physiologically acceptablederivative of prostaglandin PGA, PGB, PGD, PGE or PGF, in which theomega chain has the formula:

wherein C is a carbon atom (the number is indicated within parenthesis)B is a single bond, a double bond or a triple bond D is a chain with1-10 carbon atoms, optionally interrupted by hetero atoms O, S, or N,the substituents on each carbon atom being H, alkyl groups, preferablylower alkyl groups with 1-5 carbon atoms, a carbonyl group, or ahydroxyl group R₂ is a ring structure such as a phenyl group which isunsubstituted or has at least one substituent selected from C₁-C₅ alkylgroups, C₁-C₄ alkoxy groups, trifluoromethyl groups, C₁-C₃ aliphaticacylamino groups, nitro groups, halogen atoms, and phenyl group; or anaromatic heterocyclic group having 5-6 ring atoms, like thiazol,imidazole, pyrrolidine, thiopene and oxazole; or a cycloalkane or acycloalkene with 3-7 carbon atoms in the ring, optionally substitutedwith lower alkyl groups with 1-5 carbon atoms, for the preparation of anophtalmological composition for the treatment of glaucoma or ocularhypertension.
 2. Use according to claim 1 wherein D is a chain with 2-8carbon atoms.
 3. Use according to claim 1 wherein D is a chain with 2-5carbon atoms.
 4. Use according to claim 1 wherein D is a chain with 3carbon atoms.
 5. Use according to any of claims 1-4 wherein B is asingle bond or a double bond and the substituent on C₁₅ being a carbonylgroup or (R)—OH or (S)—OH.
 6. Use according to any of claims 1-5 whereinR₂ is a phenyl group which is unsubstituted or has at least onesubstituent selected from C₁-C₅ alkyl groups, C₁-C₄ alkoxy groups,trifluoromethyl groups, C₁-C₃ aliphatic acylamino groups, nitro groups,halogen atoms or a phenyl group.
 7. Use according to claim 6 wherein theprostaglandin derivative is a 17-phenyl-18,19,20-trinor analogue.
 8. Useaccording to claim 7 wherein the prostaglandin derivative is a15-dehydro-17-phenyl-18,19,20-trinor analogue or a13,14-dihydro-17-phenyl-18,19,20-trinor analogue.
 9. Use according toclaim 8 wherein the prostaglandin derivative is a13,14-dihydro-17-phenyl-18,19,20-trinor derivative of PGA, PGE or PGF.10. Use according to claim 8 wherein the prostaglandin is a15-dehydro-17-phenyl-18,19,20-trinor derivative of PGA, PGE or PGF. 11.Use according to any of claims 1-10 wherein the prostaglandin derivativeis an alkyl ester.
 12. A method for treating glaucoma or ocularhypertension in a subject's eye which comprises contacting the surfaceof the eye with an effective intraocular pressure reducing amount of atherapeutically active and physiologically acceptable derivative ofprostaglandin PGA, PGB, PGD, PGE or PGF in which the omega chain has theformula:

wherein C is a carbon atom (the number is indicated within parenthesis)B is a single bond, a double bond or a triple bond D is a chain with1-10 carbon atoms, optionally interrupted by hetero atoms O, S, or N,the substituents on each carbon atom being H, alkyl groups, preferablylower alkyl groups with 1-5 carbon atoms, a carbonyl group, or ahydroxyl group R₂ is a ring structure such as a phenyl group which isunsubstituted or has at least one substituent selected from C₁-C₅ alkylgroups, C₁-C₄ alkoxy groups, trifluoromethyl groups, C₁-C₃ aliphaticacylamino groups, nitro groups, halogen atoms, and phenyl group; or anaromatic heterocyclic group having 5-6 ring atoms, like thiazol,imidazole, pyrrolidine, thiopene and oxazole; or a cycloalkane or acycloalkene with 3-7 carbon atoms in the ring, optionally substitutedwith lower alkyl groups with 1-5 carbon atoms,
 13. The method of claim12 wherein D is chain with 2-8 carbon atoms.
 14. The method of claim 12wherein D is a chain with 2-5 carbon atoms.
 15. The method-of claim 12wherein D is a chain with 3 carbon atoms.
 16. The method of any ofclaims 12-15 wherein B is a single bond or a double bond and thesubstituent on C₁₅ being a carbonyl group or (R)—OH or (S)—OH.
 17. Themethod of any of claims 12-16 wherein R₂ is a phenyl group which isunsubstituted or has at least one substituent selected from C₁-C₅ alkylgroups; C₁-C₄ alkoxy groups, trifluoromethyl groups, C₁-C₃ aliphaticacylamino groups, nitro groups, halogen atoms or a phenyl group.
 18. Themethod of claim 17 wherein the prostaglandin derivative is a17-phenyl-18,19,20-trinor analogue.
 19. The method of claim 18 whereinthe prostaglandin derivative is a 15-dehydro-17-phenyl-18,19,20-trinoranalogue or a 13,14-dihydro-17-phenyl-18,19,20-trinor analogue.
 20. Themethod of claim 19 wherein the prostaglandin derivative is a15-dehydro-17-phenyl-18,19,20-trinor derivative of PGA, PGE or PGF. 21.The method of claim 20 wherein the prostaglandin derivative is a13,14-dihydro-17-phenyl-18,19-20-trinor derivative of PGA, PGE or PGF.22. The method of any of claims 12-21 wherein the prostaglandinderivative is an alkyl ester.
 23. An ophthalmological composition fortopical treatment of glaucoma or ocular hypertension which comprises aneffective intraocular pressure reducing amount of a therapeuticallyactive and physiologically acceptable prostaglandin derivative of PGA,PGB, PGD, PGE or PGF in which the omega chain has the formula:

wherein C is a carbon atom (the number is indicated within parenthesis)B is a single bond, a double bond or a triple bond D is a chain with1-10 carbon atoms, optionally interrupted by hetero atoms O, S, or N,the substituents on each carbon atom being H, alkyl groups, preferablylower alkyl groups with 1-5 carbon atoms, a carbonyl group, or ahydroxyl group R₂ is a ring structure such as a phenyl group which isunsubstituted or has at least one substituent selected from C₁-C₅ alkylgroups, C₁-C₄ alkoxy groups trifluoromethyl groups, C₁-C₃ aliphaticacylamino groups, nitro groups, halogen atoms, and phenyl group; or anaromatic heterocyclic group having 5-6 ring atoms, like thiazol,imidazole, pyrrolidine, thiopene and oxazole; or a cycloalkane or acycloalkene with 3-7 carbon atoms in the ring, optionally substitutedwith lower alkyl groups with 1-5 carbon atoms, in an ophthalmologicallycompatible carrier.